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Traditional antidepressants may take weeks to work on individuals. There have been associations with increased suicidality in some studies. The need for a more rapidly acting antidepressant is important. The study below investigated the antidepressant effect of Ketamine by looking through an FDA database and observing associations of pain and depression reduction with the use of Ketamine. They were clearly present. Of note, minocycline and Diclofenac also seemed to be associated with improved depression parameters.

Ketamine provides both pain relief and anti-depression effects in refractory patients, who by definition, have failed multiple therapies.   ::



Ketamine for Pain Management, Treatment of Depression << Article Link

Article below:

Ketamine may alleviate depression, pain, and adverse effects associated with opioid treatment, and may thus represent an attractive adjunct therapy for pain management, according to a novel population analysis recently published in Scientific Reports.1

Nearly half of all patients with depression taking conventional antidepressants discontinue their treatment prematurely.2 Researchers have sought alternatives to standard antidepressants, for which therapeutic effects are delayed by 2 to 10 weeks.3

Ketamine, an N-methyl-D-aspartate antagonist, was shown to provide acute benefits for treatment-resistant depression, bipolar depression, and major depressive disorder with suicidal ideation, when administered intravenously, however, those studies were conducted on limited samples (20 to 57 participants).4-7

The history of ketamine as an illicit drug favored for its hallucinogenic effects presents ethical obstacles to its use in large clinical trials. Researchers from the University of California San Diego in La Jolla, therefore employed an Inverse-Frequency Analysis approach to investigate whether ketamine, when administered in addition to other therapeutics, has antidepressant properties.

The team applied the inverse frequency analysis method, which looks for negative statistical patterns in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) post-marketing database of more than 8 million patient records. They observed reductions in depression and pain in patients receiving ketamine, as indicated by negative log odds ratio (logOR) values (logOR, -0.67 ± 0.034 and logOR, -0.41 ± 0.019, respectively). “The data we analyzed are indirect and skewed by cases of bad or lethal adverse effects. Nevertheless the statistics were sufficient to notice the trends,” explained study co-author, Ruben Abagyan, PhD, in an interview with Clinical Pain Advisor.

According to Dr Abagyan, a study recently published by a British team indicates that ketamine might be effective in nearly 40% of patients with severe, treatment-resistant depression, results that are concordant with those from the current study.8

The IFA method was also used to evaluate ketamine efficacy and associated side effects reported in the FAERS database. The investigators found significant reductions in a number of side effects associated with opioid therapies, including constipation (LogOR −0.17 ± 0.023), vomiting (LogOR −0.16 ± 0.025), and nausea (LogOR −0.45 ± 0.034) compared with other drug combinations used for pain management.

The authors concluded that their findings are in line with those from smaller studies, indicating beneficial effects for ketamine as a monotherapy or adjunctive therapy for depression, particularly treatment-resistant depression, with particular indication for patients with suicide ideation, because of its rapid onset of action. “The results should serve as a motivation to conduct a proper clinical trial for the rapid onset treatment of severe depression,” Dr Abagyan noted.

The novel analysis employed in this study may help investigate off-label indications for other drugs. “Ideally the method we proposed should be applied to the actual clinical data rather than the somewhat biased set of un-normalized FAERS reports,” Dr Abagyan added. “The method [can be used] to observe unexpected effects of a treatment by looking at the reduction of the baseline of this effect upon treatment. It can be applied to any effect that is being recorded including cancer, viral diseases mortality, longevity.” he concluded.



  1. Cohen IV, Makunts T, Atayee R, Abagyan R. Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indicationsSci Rep 2017;7:1450.
  2. Sansone RA, Sansone LA. Antidepressant adherence: are patients taking their medications?. Innov Clin Neurosci. 2012;9(5-6):41-46.
  3. Frazer A, Benmansour S. Mol Psychiatry. Delayed pharmacological effects of antidepressantsMol Psychiatry 2002;7:S23-8.
  4. Price RB, Iosifescu DV, Murrough JW,  et al. Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depressionDepress Anxiety 2014;31:335-343.
  5. DiazGranados N, Ibrahim LA, Brutsche NE, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorderJ Clin Psychiatry 2010;71:1605-1611.
  6. Alberich S, Martínez-Cengotitabengoa M, López P,et al. Efficacy and safety of ketamine in bipolar depression: A systematic reviewRev Psiquiatr Salud Ment 2017;10:104-112.
  7. Larkin, G. L. & Beautrais, A. L. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the emergency departmentInt J Neuropsychopharmacol 2011;8:1127-31.
  8. Singh I, Morgan C, Curran V, et al. Ketamine treatment for depression: opportunities for clinical innovation and ethical foresightLancet Psychiatry 2017;4:419-42


Population scale data reveals the antidepressant effects of Ketamine  ::  << Article below

Population scale data reveals the
antidepressant effects of ketamine
and other therapeutics approved
for non-psychiatric indications

Isaac V. Cohen, Tigran Makunts, Rabia Atayee & Ruben Abagyan

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response
and non-adherence. Here we provide new support for the antidepressant efect of an anesthetic
drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Efect
Reporting System. The results of the examination of population scale data revealed that patients who
received ketamine had signifcantly lower frequency of reports of depression than patients who took
any other combination of drugs for pain. The analysis also revealed that patients who took ketamine
had signifcantly lower frequency of reports of pain and opioid induced side efects, implying ketamine’s
potential to act as a benefcial adjunct agent in pain management pharmacotherapy. Further, the
Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant
action of other currently approved therapeutics including diclofenac and minocycline.

We found that patients listed in the FAERS database who received ketamine in addition to other therapeutics
had signifcantly lower frequency of reports of depression than patients who took any other combination of drugs
for pain (LogOR−0.67±0.034)

Te analysis of the whole FAERS database revealed several other unintentional depression reducing drugs
among antibiotics, cosmeceuticals and NSAIDS.Our data supported previous studies that observed the
psychiatric polypharmacology of minocycline, a tetracycline antibiotic.The NSAID, diclofenac, was also
observed to have some antidepressant properties.It is theorized that both of these drugs may accomplish
antidepressant effects through an anti-inflammatory mechanism.Because of the antidepressant activity of several
NSAIDs, we further separated the non-ketamine pain cohort. Ketamine patients were then compared to
patients who received any other combination of drugs for pain excluding NSAIDs. It was observed that depression
event rates remained low (LogOR−0.56±0.035).As an important side note, we also evaluated efcacy and side efects with the use of ketamine for pain management.
We found that patients who were on ketamine had reduced opioid induced side effects including constipation, vomiting, and nausea. Our data supports ketamine’s
opioid-sparing properties and alludes to the fact that patients may receive benefts of improved pain, reduced
requirement of opioids, and ultimately less opioid reduced side effects.

1. Murray, C. J. & Lopez, A. D. Evidence-based health policy–lessons from the Global Burden of Disease Study. Science 274, 740–743,
doi:10.1126/science.274.5288.740 (1996).
2. Kessler, R. C. et al. Te epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication
(NCS-R). JAMA 289, 3095–3105, doi:10.1001/jama.289.23.3095 (2003).
3. Bromet, E. et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 9, 90, doi:10.1186/1741-7015-9-90
4. Andrade, L. et al. The epidemiology of major depressive episodes: results from the International Consortium of Psychiatric
Epidemiology (ICPE) Surveys. Int J Methods Psychiatr Res 12, 3–21, doi:10.1002/(ISSN)1557-0657 (2003).
5. Sansone, R. A. & Sansone, L. A. Antidepressant adherence: are patients taking their medications? Innov Clin Neurosci 9, 41–46
6. Frazer, A. & Benmansour, S. Delayed pharmacological effects of antidepressants. Mol Psychiatry 7, S23–28, doi:10.1038/ (2002). Suppl 1.
7. Braun, C., Bschor, T., Franklin, J. & Baethge, C. Suicides and Suicide Attempts during Long-Term Treatment with Antidepressants:
A Meta-Analysis of 29 Placebo-Controlled Studies Including 6,934 Patients with Major Depressive Disorder. Psychother Psychosom
85, 171–179, doi:10.1159/000442293 (2016).
8. Seemüller, F. et al. Te controversial link between antidepressants and suicidality risks in adults: data from a naturalistic study on a
large sample of in-patients with a major depressive episode. Int J Neuropsychopharmacol 12, 181–189, doi:10.1017/
S1461145708009139 (2009).
9. Rush, A. J. et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D
report. Am J Psychiatry 163, 1905–1917, doi:10.1176/ajp.2006.163.11.1905 (2006).
10. Price, R. B. et al. Efects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant
depression. Depress Anxiety 31, 335–343, doi:10.1002/da.22253 (2014).

11. DiazGranados, N. et al. Rapid resolution of suicidal ideation afer a single infusion of an N-methyl-D-aspartate antagonist in
patients with treatment-resistant major depressive disorder. J Clin Psychiatry 71, 1605–1611, doi:10.4088/JCP.09m05327blu (2010).
12. Alberich, S. et al. Efcacy and safety of ketamine in bipolar depression: A systematic review. Rev Psiquiatr Salud Ment (2016).
13. Larkin, G. L. & Beautrais, A. L. A preliminary naturalistic study of low-dose ketamine for depression and suicide ideation in the
emergency department. Int J Neuropsychopharmacol 14, 1127–1131, doi:10.1017/S1461145711000629 (2011).
14. Miyaoka, T. et al. Minocycline as adjunctive therapy for patients with unipolar psychotic depression: an open-label study. Prog
Neuropsychopharmacol Biol Psychiatry 37, 222–226, doi:10.1016/j.pnpbp.2012.02.002 (2012).
15. Rosenblat, J. D. et al. Anti-infammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.
Bipolar Disord 18, 89–101, doi:10.1111/bdi.2016.18.issue-2 (2016).
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GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/ucm082193.htm (Accessed 2016).
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18. Questions and Answers on FDA’s Adverse Event Reporting System (FAERS)
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEfects/default.htm (Acessed 2016).



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